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Pharmacokinetics of the chemopreventive agent oltipraz and of its metabolite M3 in human subjects after a single oral dose.

Authors :
O'Dwyer PJ
Szarka C
Brennan JM
Laub PB
Gallo JM
Source :
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2000 Dec; Vol. 6 (12), pp. 4692-6.
Publication Year :
2000

Abstract

The dithiolethione oltipraz (OPZ) has activity as a chemopreventive agent in animal models and is in early clinical trials. OPZ undergoes metabolism by molecular rearrangement to yield a pyrrolopyrazine derivative, M3, which we have previously shown to be inactive in the induction of detoxication genes. M3 is metabolized further: at least 10 possible conjugates have been described in three species. We developed a new high-performance liquid chromatography method to simultaneously measure plasma concentrations of OPZ and of M3. This method was applied to serial plasma samples in a Phase I clinical trial, in which OPZ was administered at single doses varying from 125 to 1000 mg/m2. OPZ and M3 concentration-time profiles were highly variable among individuals, and the occurrence of secondary concentration peaks suggested substantial enterohepatic cycling. Absorption was rapid, and the mean time to peak was 2.2 h. Maximum plasma concentration values were proportional to the dose. Harmonic mean half-lives at these doses ranged from 9.3-22.7 h. There were indications of dose-dependent pharmacokinetic properties because apparent clearance and volume of distribution at steady state increased with dose, although these changes were not statistically significant as a result of high interpatient variability. Accordingly, there were less than proportional increases in the OPZ and M3 area under the curve and maximum plasma values. Interpretation of OPZ and M3 disposition is confounded by the unknown bioavailability factor; however, the most likely inferences are that bioavailability of OPZ decreases with increasing dose and that metabolism to M3 is saturable.

Details

Language :
English
ISSN :
1078-0432
Volume :
6
Issue :
12
Database :
MEDLINE
Journal :
Clinical cancer research : an official journal of the American Association for Cancer Research
Publication Type :
Academic Journal
Accession number :
11156221